Drug Release Parameters Research Articles

COMPARATIVE EFFICIENCY OF FORMULATION TECHNIQUES FOR DEVELOPMENT OF SALBUTAMOL SULPHATE LOADED LIPOSOMES

Present study investigate d most efficient technique for the develop ment of salbutamol sulphate loaded liposom es . Salbutamol sulphate is a selective β 2 adrenoceptor agonist widely used in the treatment of bronchial asthma, chronic bronchitis and emphysema. Our work is mainly focused on in vitro st udies of liposomal formulation encapsulated with salbutamol sulphate which may have high drug entrapment, sustained drug release and effective vesicle size. Drug loaded liposome s were prepared by ethanol injectio n and thin film hydration techniques using s oyaphosphatidyl choline and cholesterol in various molar ratios . Liposomes were evaluated for vesicle size, entrapment efficiency, transmission electron microscopy, zeta potential and drug release parameters. The particle size of drug loaded liposomes prep ared by ethanol injection technique was 423 ‐ 527 nm whereas it was 160 - 174.2 nm when prepared by thin film hydration technique. Z eta potential of liposomes prepared by thin film hydration technique was enough to stabilize over six month s . Optimized batches of s albutamolsulphate loaded liposomal formulations prepared by ethanol injection and thin film hydration technique have shown drug release as 94.59 % and 88.03 %, respectively . On the basis of observed a verage particle size, percent drug entrapment and dr ug release profiles, thin film hydration technique was emerged as superior technique over ethanol injection technique.

Formulation and Evaluation of Nicorandil Sustained Release Matrix Tablets Using Natural Gum Mangifera Indica as Release Modifier

The purpose of the present study was to formulate the nicorandil sustained release matrix tablets by using Mangifera indica gum as rate controlling factor and to evaluate drug release parameters as per various release kinetic models. The Mangifera indica gum is extracted and evaluated for physicochemical and phytochemical property using official procedures. The tablets were prepared by wet granulation method. The granules were evaluated for angle of repose, loose bulk density, tapped bulk density and compressibility index, showed satisfactory results. All the granules were lubricated and compressed and were evaluated for uniformity of weight, content of active ingredient, thickness, friability, hardness and In-vitro dissolution studies. Fourier transform infrared (FTIR) study revealed that there was no chemical interaction between drug and the gum used. All the formulation showed compliance with Pharmacopoeial standards. In-vitro drug release studies were carried out using USP 35/NF 30 dissolution apparatus type II at 50 rpm (rate per minute). The in-vitro release study of matrix tablets were carried out for 12 h. The prepared matrix tablets were shown 97.8%, 96.5%, 96.8%, 90.7% and 86.5% release over a period of 12 h. A better sustained drug release of 96.8% was obtained with formulation F3 at the end of 12 h. Optimized formulation F3 was subjected to stability studies for three months, which showed stability with respect to release pattern. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets was dependent on gum concentration and it was found to be diffusion coupled with erosion.

Formulation and Evaluation of Phenytoin Sodium Sustained Release Matrix Tablet

Epilepsy is a very common disorder, characterized by seizures, which take various forms and result from episodic neuronal discharges, the form of the seizure depending on the part of the brain affected. There is no recognition cause, although it may develop after brain damage, such as trauma, infection or trauma, and other kinds of neurological diseases. Epilepsy is treated mainly with drugs, though brain surgery may be used for severe cases. Sodium channel blockers are generally used in the treatment of seizures, e.g.: phenytoin, carbamazepine, sodium valproate. The aim of this study is to develop sustained release matrix tablet of phenytoin sodium using eudragit- RL100, eudragit-RS100, HPMC-E15, ethyl cellulose (N-14), Chitosan and HPMC as release controlling factor and to evaluate drug release parameters as per various release kinetic models. The formulated tablets were also characterized by physical and chemical parameters and results were found in acceptable limits. Different dissolution models were applied to drug release data in order to evaluate release mechanisms and kinetics. Criteria for selecting the most appropriate model were based on linearity (coefficient of correlation). Based on “n” value (0.168) the drug release was follows Fickian diffusion. Also the drug release mechanism was best explained by Higuchi order (correlation value is 0.9063) by using this polymer.

Formulation Development and in vitro Evaluation of Drug Release Kinetics from Sustained Release Aceclofenac Matrix Tablets using Hydroxypropyl Methyl Cellulose

The objective of the present study was to develop a once-daily sustained release matrix tablet of Aceclofenac using hydroxypropyl methyl cellulose (Methocel K 100M CR) as release controlling factor and to evaluate drug release parameters as per various release kinetic models. The tablets were prepared by direct compression method. The powder blends were evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index, total porosity and drug content etc. The tablets were subjected to thickness, weight variation test, drug content, hardness, friability and in vitro release studies. The in vitro dissolution study was carried out for 24 hours using United States Pharmacopoeia (USP) 22 paddle-type dissolution apparatus in phosphate buffer (pH 7.4). The powder blends showed satisfactory flow properties, compressibility index and drug content etc. All the tablet formulations showed acceptable pharmacotechnical properties and complied with pharmacopoeial specifications. The results of dissolution studies indicated that the formulation F-3 (40% Methocel K100M CR of total weight of tablet) could extend the drug release up to 24 hours and the total release pattern was very close to the theoretical release profile. By comparing the dissolution profiles with the originator brand of Arrestin SR, the formulation F-3 exhibited drug release profile like originator brand. From this study, a decrease in release kinetics of the drug was observed by increasing the polymer concentration. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport, which was only dependent on the type and amount of polymer used. The drug release followed both diffusion and erosion mechanism in all cases. The drug release from the formulation (F-3) was satisfactory after 3 months storage in 400C and 75% RH. Besides, this study explored both of the optimum concentration and effect of polymer(s) on Aceclofenac release pattern from the tablet matrix for 24 hour period. The matrix tablet of Aceclofenac using HPMC with molecular weight of K100M controlled the drug release effectively for 24 hours; hence the formulation can be considered as a once daily sustained release tablet of Aceclofenac in order to improve patient compliance. DOI: http://dx.doi.org/10.3329/dujps.v11i1.12485 Dhaka Univ. J. Pharm. Sci. 11(1): 37-43, 2012 (June)

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

Self-nanoemulsifying drug delivery system for adefovir dipivoxil: Design, characterization, in vitro and ex vivo evaluation

Adefovir dipivoxil (ADV) is an anti-viral drug having low bioavailability due to low permeability and pH dependent solubility. In this study, self-nanoemulsifying drug delivery systems (SNEDDS) of ADV were developed with the objective of increasing its bioavailability by enhancing its intestinal permeability and minimizing the effect of pH. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. The nanoemulsion system selected from the phase diagram was transformed into solid-SNEDDS (S-SNEDDS) by lyophilization using D-mannitol as cryoprotectant. The formulations were characterized for transmittance, globule size, polydispersity index, zeta potential, cloud point, robustness to dilution, effect of pH and temperature, microscopic properties, in vitro and ex vivo drug release parameters. The liquid SNEDDS (L-SNEDDS) showed mean globule size of 110 ± 10 nm while mean globule size of 150 ± 16 nm was obtained with S-SNEDDS. The formulations were found to be robust to dilution and showed cloud point at 80–85 °C. TEM and SEM studies of nanoemulsion reconstituted from S-SNEDDS demonstrated the spherical shape and size of the globules. Results of DSC and XRD studies confirmed that the drug was incorporated in the S-SNEDDS. No significant difference was observed in the globule size within physiological variations of pH and temperature. The in vitro and ex vivo drug release from ADV SNEDDS was found to be significantly higher in comparison to that from plain drug suspension, irrespective of pH. Thus, SNEDDS were found to be instrumental in reducing the effect of pH variability of ADV and improving the release performance of ADV, indicating their potential to improve the oral bioavailability and thus the therapeutic efficacy of ADV.

Analysis of pharmaceutical pellets: An approach using near-infrared chemical imaging

Pharmaceutical pellets are spherical or nearly spherical multi-unit dosage forms designed to optimize pharmacokinetics and pharmacodynamics features of drug release. The distribution of the pharmaceutical ingredients in the layers and core is a very important parameter for appropriate drug release, especially for pellets manufactured by the process of layer gain. Physical aspects of the sample are normally evaluated by Scanning Electron Microscopy (SEM), but it is in many cases unsuitable to provide conclusive chemical information about the distribution of the pharmaceutical ingredients in both layers and core. On the other hand, methods based on spectroscopic imaging can be very promising for this purpose. In this work, a Near-Infrared Chemical Imaging (NIR-CI) method was developed and applied to the analysis of diclophenac sodium pellets. Since all the compounds present in the sample were known in advance, Classical Least Squares (CLS) was used for calculations. The results have shown that the method was capable of providing chemical information about the distribution of the active ingredient and excipients in the core and coating layers and therefore can be complementary to SEM for the pharmaceutical development of pellets.

Design and Evaluation of Controlled-Release Niosomes and Discomes for Naltrexone Hydrochloride Ocular Delivery

This study aimed at preparing and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearyl amine (STA)] and surfactants [poly-24-oxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepared using four different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2%-5% mol/mol additives. Differential scanning calorimetry thermograms revealed that the additives completely abolished gel/liquid transition suggesting that the bilayer membranes could accommodate the additives. The volume diameters D (4, 3) of the prepared niosomes were significantly [p < 0.05, analysis of variance (ANOVA)] dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 ± 1.40 and 5.37 ± 1.40 μ m, respectively. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepared niosomes significantly (p < 0.01, ANOVA) controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepared niosomal formulations were found practically nonirritant when applied onto the surface of a 10-day-old hen's chorioallantoic membrane.

Dissolution Method for Milnacipran Hydrochloride Capsules: Development, Validation, and Study of Changes in Dissolution Rate after Storage

A dissolution test for milnacipran hydrochloride capsules was developed and validated according to international guidelines. After selection of the best conditions, the method was validated using USP Apparatus 1 (baskets), 50-rpm rotation speed, 900 mL of 0.01 N HCl, and test time of 60 min. The drug released was determined by both LC–UV (PDA) and UV–D methods. The kinetic parameters of drug release (mathematical models, t80%, and dissolution efficiency) were investigated, and the stability of the dosage form was evaluated by analyzing changes in the dissolution rate of milnacipran hydrochloride capsules during storage at 40 °C and 75% RH for different periods. INTRODUCTION Dissolution testing can provide information not only on the rate and extent of drug absorption in the body but also on the effects of drug biopharmaceutical properties and formulation principles on the release properties of a pharmaceutical product (1). Therefore, in vitro dissolution tests are usually used to assess the lot-to-lot quality of a drug product, guide development of new formulations, an d ensure continued product quality and performance after certain changes such as formulation, manufacturing process, site of manufacture, and the scale-up of the manufacturing process (2). The dissolution procedure requires an apparatus, a dissolution medium, and test conditions that provide a method that is discriminating yet sufficiently rugged and reproducible for day-to-day operation and capable of being transferred between laboratories. With regard to stability, the dissolution test should appropriately reflect relevant changes in the drug product caused by temperature, humidity, photosensitivity, and other stresses over time (3). Milnacipran hydrochloride (MNC), [101152-94-7], C15H22N2O⋅HCl, molecular weight 282.81 g/mol (Figure 1), is a racemic mixture with the chemical name (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride, and its solubility in water is 19 mg/mL (4–6). MNC is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated as an antidepressant and for the management of fibromyalgia. It shows preferential blockade of norepinephrine reuptake over serotonin and minimal activity at other receptors or transporters (6–8). MNC is well absorbed after oral administration with maximum concentrations reached within 2–4 h, and its absorption is not affected by food. It presents an absolute bioavailability of approximately 85–90% (9). The solubility and absolute bioavailability data for this drug classify it as Class I (high solubility and high permeability) based on the Biopharmaceutical Classification System. This is the case where the drug is well absorbed, and for immediate-release dosage forms that dissolve very rapidly, the absorption rate is controlled by the gastric emptying rate, and some correlation with dissolution rate is expected only if the dissolution is slower than gastric emptying (10). Methods for quantitation of milnacipran in combination with other antidepressants and their metabolites in biological fluids have been proposed (11–17). However, there is no compendial method to assay milnacipran hydrochloride in pharmaceutical dosage forms. A stability-indicating liquid chromatographic method with UV detection (LC–UV) and a second-order derivative UV spectroscopic method (UV–D) for quality control of milnacipran in capsules were developed and validated by the authors (18) according to guidelines (19–21). Therefore, the purpose of this work was to develop and validate a dissolution test for MNC in capsules (50 mg) based on its physicochemical characteristics and apply the LC–UV and UV–D methods to quantify the drug released from the capsules during the dissolution procedure. The kinetic parameters of drug release were investigated, and the stability of the dosage form was evaluated by analyzing changes in the dissolution rate of MNC capsules over time and in various storage conditions. EXPERIMENTAL Chemicals Milnacipran hydrochloride was purchased from Synfine Research (Canada). The pharmaceutical dosage form *Corresponding author. diss-18-03-06.indd 47 8/31/2011 1:38:15 PM dx.doi.org/10.14227/DT180311P47

Preparation and evaluation of mucoadhesive hydrophilic hydroxy propyl methyl cellulose based extended release matrix tablets of Niacin (Nicotinic acid)

The aim of this study is to develop a once-daily extended release matrix tablet of Niacin using Hydroxy Propyl Methyl Cellulose i.e. Methocel K4M CR as release controlling factor and to evaluate drug release parameters as per various release kinetic models and also to find the best fitted extended release matrix formulation of Niacin. In order to achieve required extended release profile, tablets were prepared by wet granulation technique using different formulations (F-1, F-2, F-3, F-4, F-5 and F-6) with different amount of Methocel K4M CR. The formulated tablets were also characterized by physical and chemical parameters and results were found in acceptable limits. Different release kinetic models were applied in order to evaluate release of Niacin from the prepared matrix tablets. Criteria for selecting the most appropriate model were based on linearity (coefficient of correlation) and diffusion exponent of the respective kinetic model. Among all the formulations, F-5 was found as the best fitted matrix tablet for extended release of Niacin. Drug release mechanism was found as a complex mixture of diffusion, swelling and erosion.

Development and Validation of a Discriminating In Vitro Dissolution Method for a Poorly Soluble Drug, Olmesartan Medoxomil: Comparison Between Commercial Tablets

A dissolution test for tablets containing 40 mg of olmesartan medoxomil (OLM) was developed and validated using both LC-UV and UV methods. After evaluation of the sink condition, dissolution medium, and stability of the drug, the method was validated using USP apparatus 2, 50 rpm rotation speed, and 900 ml of deaerated H(2)O + 0.5% sodium lauryl sulfate (w/v) at pH 6.8 (adjusted with 18% phosphoric acid) as the dissolution medium. The model-independent method using difference factor (f(1)) and similarity factor (f(2)), model-dependent method, and dissolution efficiency were employed to compare dissolution profiles. The kinetic parameters of drug release were also investigated. The obtained results provided adequate dissolution profiles. The developed dissolution test was validated according to international guidelines. Since there is no monograph for this drug in tablets, the dissolution method presented here can be used as a quality control test for OLM in this dosage form, especially in a batch to batch evaluation.

Evaluation of Mixing Process of Magnesium Stearate as Lubricant and the Spatial Distribution of Chemical Components in a Tablet by Vibrational Spectroscopic Imaging

In the work presented in this paper, a mixing procedure for a tableting process was evaluated using a simple formulation with Magnesium Stearate as the lubricant. Assessment of the spatial distribution of chemical components in a tablet can be effectively accomplished by Vibrational Spectroscopic Imaging techniques that employ Raman spectroscopy and NIR spectroscopy.We show that, by selecting the proper rotation speed for the high speed mixer selected, similar drug release and tablet hardness parameters can be achieved between a tumbling type mixer and a twin shell mixer. Additionally by changing the time of mixing we can produce samples from both mixing methods with similar drug release rates. We relate these release rates to the hardness of the tablets, the tablet and, ultimately, to the distribution and particle size of the drug and lubricant on the surface of the tablets evaluated using the spectroscopic imaging techniques cited above.

Drug–polymer microparticles produced by supercritical assisted atomization

The supercritical assisted atomization (SAA) was proposed as a new technique to produce composite microparticles for drug controlled release. Ampicillin trihydrate and chitosan were selected as model drug and carrier, respectively, and 1% v/v acetic acid aqueous solution was used as solvent. The effect of the polymer/drug ratio on particle morphology and drug release rate was evaluated. SEM analysis indicated that non-coalescing spherical microparticles formed by chitosan/ampicillin were produced by SAA. All coprecipitates produced have a sharp particle distribution, with diameters ranging between about 0.1 and 6 microm. SAA composite microparticles were characterized by X-ray, DSC, EDX and UV-vis analysis. A solid solution of the chitosan and ampicillin was produced and a stabilizing effect of the polymer on the drug has resulted that protects ampicillin from thermal degradation. A prolonged release from SAA coprecipitates with respect to raw drug and physical mixtures of chitosan and ampicillin was obtained; moreover, the polymer/drug ratio has revealed to be a controlling parameter for drug release. Drug release mechanisms characteristic of swelling-controlled systems were observed, with ampicillin release depending on both relaxation and diffusive mechanisms. An empirical binomial equation was used to describe experimental data, showing a fair good agreement with ampicillin release data if both the relaxational and the diffusional parameters are function of the polymer/drug ratio.

Effect of lactide/glycolide ratio on the in vitro release of ganciclovir and its lipophilic prodrug (GCV-monobutyrate) from PLGA microspheres

Purpose The aim of this study is to investigate the roles of the lactide/glycolide ratio and prodrug derivatization on the in vitro release of ganciclovir and its lipophilic prodrug (GCV-monobutyrate) from PLGA microspheres for the treatment of cytomegalovirus (CMV) retinitis. Method Two grades of PLGA, a higher lactide content PLGA 6535 [ d, l-lactide:glycolide = 65:35, MW 45,000–75,000 Da] and lower lactide content PLGA 5050 [ d, l-lactide:glycolide = 50:50, MW 45,000–75,000 Da] were employed to prepare GCV loaded microspheres. The effect of lipophilic prodrug derivatization was investigated by converting GCV to GCV-monobutyrate (GCVMB). Microspheres were prepared by the oil-in-oil (O/O) solvent evaporation method and characterized in vitro, by studying their surface/internal morphology, entrapment efficiency, particle size, drug release, true density and glass transition temperature. In vitro release data were analyzed by a model equation to estimate various parameters of the drug release curves. Results The O/O solvent evaporation method generated a high drug payload of up to 91%. Higher entrapment efficiencies were observed in the case of hydrophilic drug (GCV) relative to the lipophilic prodrug (GCVMB). Loosely bound or surface adsorbed drug/prodrug molecules may have resulted in the very short period (about 6 h) of the initial burst phase in all types of microspheres. GCV loaded microspheres utilized more time to release 50% ( T 50 value) of entrapped drug than GCVMB microspheres. T 50 values estimated for GCVMB were shorter than those for GCV from microspheres with similar lactide/glycolide ratios. Lactide content in PLGA did not significantly alter GCVMB release relative to GCV release. The proposed model equation effectively estimated the drug release parameters ( R 2 > 0.98) with all drug/prodrug-PLGA combinations. SEM pictures have revealed that although both GCV and GCVMB microspheres were spherical but internal morphology was different, with former having uniform and dense whereas later have porous structures. Corroborating with internal morphologies, results revealed that true densities of GCV microspheres were relatively greater than corresponding GCVMB microspheres. Conclusion The proposed method of preparation yields higher efficiency of drug entrapment for the hydrophilic drug. Prodrug entrapment into microspheres could result in longer residence time at the site of administration due to multiple processes involved in drug release at infected tissue. These processes include release from microspheres and enzymatic conversion of the prodrug to parent drug.

Effect of Polymer Blending on the Release of Ganciclovir from PLGA Microspheres

The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer RG 502H [D,L-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R2 values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70-95%) was released during the matrix degradation cum diffusion phase. Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502HColon, two colons 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.

Tumour cell delivery of antisense oligonuclceotides by human serum albumin nanoparticles

Nanoparticles consisting of human serum albumin (HSA) and containing different antisense oligonucleotides (ASO) were prepared by desolvation. The preparation process was optimised regarding the amount of desolvating agent, stabilisation conditions as well as nanoparticle purification. The glutaraldehyde crosslinking procedure of the particle matrix was identified as a crucial parameter for biodegradability and drug release of the nanoparticles. The influence of chain length and backbone modification of ASOs on the drug loading efficiency was investigated. The loading increased with longer chain length and employment of a phosphorothioate backbone. The resulting nanoparticles were tested in cell cultures for cytotoxicity and cellular uptake. In different tumour cell lines no cytotoxic effect was observed up to nanoparticle concentrations of 5000 μg/ml. All cell lines showed a significant cellular uptake of HSA nanoparticles. The entrapment of a fluorescent labelled oligonucleotide within the particle matrix was used for the detection of the intracellular drug release of the carrier systems. Confocal laser scanning microscopy revealed that nanoparticles crosslinked with low amounts of glutaraldehyde, rapidly degraded intracellularly, leading to a significant accumulation of the ASO in cytosolic compartments of the tumour cells.

Parameters to be Considered in the Simulation of Drug Release from Aspirin Crystals and their Microcapsules

Purpose: Drug microparticles may be microencapsulated with water-insoluble po lymers to obtain controlled release, which may be further determined by the pa rticle d istribution. The purpose o f t his s tudy was to de termine the drug release pa rameters needed for the theoretical prediction of the release profiles of single aspirin crystals and their microcapsules. Method: Four single crystals of aspirin of varied weight and orthorhombic in shape or their microcapsules also of varied weights were randomly selected for the study. The microcapsules were walled with an acrylatemethacrylate copolymer ( wall thickness, 11 i m). The following parameters were evaluated: the order of release, the dissolution rate constant, k (crystals), the diffusion coefficient, D (microcapsules), the maximum release m∞ and time to attain it t∞. These parameters were in turn used to simulate the release profiles of hypothetical single particles of a wide range size distribution, 0.3 ‐ 1.4 mm at 0.1mm intervals. Results: The e mpirical single crystals exhibited an initial zero o rder ( 93%; dissolution constant = 4.4 min -1 ) followed by a first order release (6%; dissolution constant = 0.38 min -1 ). Maximum release from each of the crystals was 99% of the initial particle weight; thus m∞ was a constant fraction of the initial particle weight. A zero order release consistent with a Fickian diffusion model was displayed b y the single microcapsules (diffusion coefficient, 5.4x10 -4 mm 2 min -1 ). At same particle weight the release parameters m∞, t∞, and the slopes of the rate order plots compared favourably with the theoretical data. Conclusion: The study indicates that the empirical release data on a few single particles can be used to predict the release profiles of single particles of a wide range of size distribution. This finding may be exploited in the prediction of drug release from polydisperse systems.

An Investigation of the Mechanism of Release of the Amphoteric Drug Amoxycillin from Poly(d,l-Lactide-co-glycolide) Matrices

Amoxycillin–poly (d,l-lactide-co-glycolide) (PLGA) compacts were prepared by direct compression of both powder mixtures or films in a pre-heated press. Release profiles generally showed two phases separated by an induction period. Thus, both diffusion and polymer degradation mechanisms were involved in drug release, the relative importance of each depending on processing type and drug loading. Drug release parameters for each phase were determined. The fraction of total drug released, in the initial release phase, increased with drug loading and was much larger for compressed physical mixtures than for compressed composites prepared from co-evaporate films. Comparison of the polymer mass loss profiles of drug-loaded and drug-free discs indicated that the presence of the amphoteric drug amoxycillin had little impact on the polymer degradation rate, in contrast to the marked acceleration previously reported for basic drugs. Significant drug degradation occurred and was associated with release at later times. Release data was fitted to an equation accounting for degradation of the drug on release and suggested accelerated amoxycillin degradation during the polymer degradation controlled release phase, consistent with changes in pH in the microenvironment of the eroding compact.

Influence of drug:hydroxypropylmethylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets

This study evaluates the relationship and influence of formulation and technological factors such as drug:hydroxypropylmethylcellulose (HPMC) ratio, particle size of the drug, particle size of HPMC and compression force, on drug release from matrices containing HPMC and diclofenac sodium as a model drug. The influence of these variables was assessed by multi-way analysis of variance. The results of the present study point out that the rate and mechanism of diclofenac sodium release from HPMC K15M matrices are mainly controlled by the drug:HPMC ratio. The drug and HPMC particle size also influence the drug release parameters, although to a lesser extent. Finally, the independence of the drug release from matrix tablets with respect to the compression force is reported.

Drug release evaluation of diltiazem CR preparations

The objectives of this study were (a) to evaluate the effects of dissolution medium pH and dosage form structural integrity on the release mechanisms and kinetics of Diltiazem HCl (DLTZ) from peroral CR/SR preparations, and (b) to evaluate the CR/SR products comparatively for their drug release parameters. Four marketed CR/SR products of DLTZ were used in the study. Different dissolution models were applied to drug release data in order to evaluate release mechanisms and kinetics. Criteria for selecting the most appropriate model was based on best goodness of fit, smallest sum of squared residuals and F-statistics. Marked differences in dissolution characteristics of three preparations were observed in different dissolution media of pH between 1.2 and 8.0. Based on the best fit of release data to different mathematical models an attempt was made to elucidate the mechanism of drug release. Drug release parameters (duration of drug release, release rate), expected steady state plasma drug concentrations and dosage form index were calculated and compared with theoretical controlled release parameters developed based on the pharmacokinetic characteristics of the drug.